Submissions for variant NM_024675.4(PALB2):c.304G>A (p.Val102Ile)

gnomAD frequency: 0.00002  dbSNP: rs778573607

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465446	SCV000550685	uncertain significance	Familial cancer of breast	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 102 of the PALB2 protein (p.Val102Ile). This variant is present in population databases (rs778573607, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 410149). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000562562	SCV000665186	likely benign	Hereditary cancer-predisposing syndrome	2022-08-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Myriad Genetics, Inc.	RCV000465446	SCV004018653	likely benign	Familial cancer of breast	2023-06-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
GeneDx	RCV003332178	SCV004040305	uncertain significance	not provided	2023-03-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31382929, 20871615, 19369211)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003332178	SCV004222334	uncertain significance	not provided	2023-06-30	criteria provided, single submitter	clinical testing	To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00014 (5/34530 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.